The immuno-modulatory effects of radiotherapy (RT) associated with anti-tumor immunity have recently become a focus of investigations in a range of indications. Meanwhile, the radiation dose, fractionation and timing on clinical trials has been highly variable. A concerted approach to determine the radiation regimen needed to stimulate the immune system in humans is needed. Animal experiments have confirmed the existence a synergy between immunotherapy and radiation, but it is unclear how these results translate to patients in terms of dose, sequencing, timing and fractionation. The objective of this proposal is to develop a novel bio-physical approach to derive the synergism of radiotherapy with immunotherapy directly, i.e. without using parameters derived from animal experiments, from clinical patient and outcome data. The model is based on observable patient information, such as tumor load and circulating lymphocyte counts, and will be validated using clinical trial data from our institution. In SA1 we will first develop the tumor-immune-radiation model, enabling us to predict the lymphocyte depleting effect of radiation and the tumor-lymphocyte interaction, validated by clinical data of hepatocellular carcinoma (HCC) patients treated with radiotherapy. Most importantly, we will be able to simulate the effect of different fractionation regimen on the circulating lymphocyte count. In SA2 we will include the effect of immunotherapy based on HCC patient data and validate the combined approach by predicting the results of an innovative Immuno-RT trial currently conducted at our institution. We will subsequently apply the model to investigate optimal dose & fractionation regimen and their dependence upon patient characteristics in the treatment of locally advanced and metastatic HCC.